Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita

Aplastic Anemia Clinical Trial

Official title:

Radiation- and Alkylator-free Hematopoietic Cell Transplantation for Bone Marrow Failure Due to Dyskeratosis Congenita / Telomere Disease

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01659606
• Other study ID #: 12-950
• Secondary ID: IRB-P00003466
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: July 2012
• Est. completion date: December 2034

Study information

• Verified date: February 2024
• Source: Boston Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Dyskeratosis congenita is a disease that affects numerous parts of the body, most typically causing failure of the blood system. Lung disease, liver disease and cancer are other frequent causes of illness and death. Bone marrow transplantation (BMT) can cure the blood system but can make the lung and liver disease and risk of cancer worse, because of DNA damaging agents such as alkylators and radiation that are typically used in the procedure. Based on the biology of DC, we hypothesize that it may be possible to avoid these DNA damaging agents in patients with DC, and still have a successful BMT. In this protocol we will test whether a regimen that avoids DNA alkylators and radiation can permit successful BMT without compromising survival in patients with DC.

Description:

Dyskeratosis congenita (DC) is an inherited multisystem disorder, which classically presents with a clinical triad of skin pigment abnormalities, nail dystrophy, and oral leukoplakia. DC is part of a spectrum of telomere biology disorders, which include some forms of inherited idiopathic aplastic anemia, myelodysplastic syndrome, and pulmonary fibrosis and the congenital diseases Hoyeraal-Hreidarsson syndrome and Revesz syndrome. Progressive bone marrow failure (BMF) occurs in more than 80% of patients under 30 years of age and is the primary cause of morbidity and mortality, followed by pulmonary failure and malignancies. Allogeneic hematopoietic cell transplantation (HCT) is curative for the hematological defects, but several studies have demonstrated poor outcomes in DC patients due to increased early and late complications. A predisposition to pulmonary failure, vascular disease and secondary malignancies may contribute to the high incidence of fatal complications following HCT in DC patients, and provides an impetus to reduce exposure to chemotherapy and radiotherapy in preparative regimens. Recent studies suggest that fludarabine-based conditioning regimens provide stable engraftment and may avoid the toxicities seen after HCT for DC, but studies to date are limited to case reports, retrospective studies and a single prospective trial. In this study, we propose to prospectively evaluate the efficacy of a fludarabine- and antibody-based conditioning regimen in HCT for DC patients, with the goals of maintaining donor hematopoiesis and transfusion independence while decreasing early and late complications of HCT for DC.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 40
• Est. completion date: December 2034
• Est. primary completion date: April 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Days to 65 Years

Eligibility

Inclusion Criteria:

• Bone marrow hypocellular for age

• Moderate or severe aplastic anemia defined by one of the following: peripheral blood neutrophils < 0.5 x 10^9/L; platelets < 30 x 10^9/L or platelet transfusion dependence; reticulocytes < 50 x 10^9/L in anemic patients or red cell transfusion dependence

• Diagnosis of dyskeratosis congenita based on clinical triad of abnormalities of skin pigmentation, nail dystrophy, oral leukoplakia; OR one of clinical triad and presence of two or more associated features; OR a pathogenic mutation in DKC1,TERC, TERT, NOP10, NHP2, TCAB1, TINF2, CTC1, PARN, RTEL1, ACD, NAF1, STN1, or ZCCHC8, as reported by a CLIA-approved laboratory; OR age-adjusted mean telomere length < 1%ile in peripheral blood lymphocytes as reported by a CLIA-approved laboratory; OR Hoyeraal-Hreidarsson syndrome; OR Revesz syndrome

• Availability of a related or unrelated donor with a 7/8 or 8/8 match for HLA-A, B, C, and DRB1.

• Patient and/or legal guardian must be able to sign informed consent.

• Donor must provide a marrow allograft.

• Diagnosis of Fanconi anemia must be excluded by mitomycin C or diepoxybutane chromosomal breakage testing on peripheral blood at a CLIA-approved laboratory (not required for patients with a genetic mutation consistent with DC)

• Adequate renal function with glomerular filtration rate equal to or greater than 30 ml/min/1.73 m2

Exclusion Criteria:

• Clonal cytogenetic abnormalities associated with MDS or AML on bone marrow examination.

• Karnofsky/Lansky performance status < 40.

• Uncontrolled bacterial, viral or fungal infections.

• Positive test for the human immunodeficiency virus (HIV).

• Pregnancy or breastfeeding.

• Known severe or life-threatening allergy or intolerance to fludarabine, alemtuzumab, mycophenolate mofetil or both cyclosporine and tacrolimus.

• Positive patient anti-donor HLA antibody, which is deemed clinically significant.

• Prior allogeneic marrow or stem cell transplantation.

• Prior solid organ transplantation.

Related Conditions & MeSH terms

• Anemia, Aplastic
• Aplastic Anemia
• Dyskeratosis Congenita
• Hoyeraal Hreidarsson Syndrome
• Revesz Syndrome
• Syndrome

Intervention

Biological:
• alemtuzumab
Conditioning: alemtuzumab 0.2 mg/kg/dose IV/SC x 5 doses

Drug:
• Fludarabine
fludarabine 30 mg/m2/dose IV x 6 doses
• Cyclosporins

• Mycophenolate mofetil

• Tacrolimus

Locations

Country	Name	City	State
Norway	Oslo University Hospital	Oslo
Sweden	Karolinska University Hospital	Stockholm
United States	Boston Children's Hospital (pediatric patients)	Boston	Massachusetts
United States	Dana-Farber Cancer Institute (adult patients)	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Duke University Medical Center, Pediatric BMT	Durham	North Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Baylor College of Medicine	Houston	Texas
United States	Children's Mercy Hospital Kansas City	Kansas City	Missouri
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	Fred Hutch/University of Washington/Seattle Children's Cancer Consortium	Seattle	Washington

Sponsors (16)

Lead Sponsor

Collaborator

Boston Children's Hospital

Baylor College of Medicine, Children's Hospital Los Angeles, Children's Hospital Medical Center, Cincinnati, Children's Hospital of Philadelphia, Children's Mercy Hospital Kansas City, Dana-Farber Cancer Institute, Duke University, Fred Hutch/University of Washington/Seattle Children's Cancer Consortium, Hackensack Meridian Health, Karolinska University Hospital, Massachusetts General Hospital, Mayo Clinic, Oslo University Hospital, University of Chicago, University of Wisconsin, Madison

Countries where clinical trial is conducted

United States,  Norway,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Primary engraftment		Up to day +100 post-BMT
Secondary	Survival to day+100 post-BMT		Up to day+100 post-BMT
Secondary	Viral reactivation and infection	Number of participants with DNA virus (cytomegalovirus, Epstein Barr virus, or adenovirus) reactivation/infection detected by PCR screening will be reported.	Up to day +100 post-BMT
Secondary	Treatment related adverse events as assessed by CTCAE version 4.0		Up to 1 year post-BMT
Secondary	Secondary graft failure		Up to 15 years post-BMT
Secondary	Acute and chronic graft-versus-host disease (GVHD)		Up to 15 years post-BMT
Secondary	Engraftment monitoring (chimerism)		Up to 15 years post-BMT
Secondary	Immune reconstitution as assessed by quantitation of lymphocyte subsets	Number of participants with quantitative defects in lymphocyte subset numbers following BMT	Up to 15 years post-BMT
Secondary	Changes in pulmonary function as assessed by pulmonary function testing		Up to 15 years post-BMT
Secondary	Secondary malignancies	Number of patients with malignancies following BMT	Up to 15 years post-BMT
Secondary	Long-term survival		Up to 15 years post-BMT